Contribution of inflammation and proinflammatory cytokines in the development of endothelial dysfunction

Coronary microvascular dysfunction (CMD) comprises of three major mechanisms: enhanced coronary vasoconstrictive reactivity (e.g., coronary spasm) at the epicardial and microvascular levels, impaired endothelium-dependent and -independent coronary vasodilator capacity, and increased coronary microvascular resistance induced by structural factors (e.g., luminal narrowing, vascular remodelling, vascular rarefaction and extramural compression). 

The endothelium is pivotal in the vascular tone modulation by synthesising and releasing endothelium-derived relaxing factors (EDRFs), such as vasodilator prostaglandins, nitric oxide (NO) and endothelium-dependent hyperpolarisation (EDH) factors, in a distinct vessel size-dependent manner. NO predominantly mediates the vasodilatation of the large, conduit vessels (the aorta and epicardial coronary arteries), whereas EDH factors mediate vasodilatation of the small resistance vessels (arterioles and coronary microvessels).¹

Inflammation and proinflammatory cytokines are involved in the development of endothelial dysfunction. Given that EDH factors, rather than NO, predominantly mediate the endothelium-dependent vasodilatation of resistance arteries, this is an important mechanism, especially in the microcirculation, where blood pressure and organ perfusion are finely tuned to meet the bodily fluctuating demands. Inflammation is associated with a reduction in the production and/or action of EDRFs.¹A positive association between higher serum levels of interleukin (IL)-1 receptor antagonist and an increased incidence of cardiovascular disease has been described in the general population.²

Inflammation is closely related to the perivascular adipose tissue (PVAT). Studies by Nishimiya and Ohyama have revealed close relations between inflammation, PVAT and vasa vasorum, in the pathogenesis of coronary vasomotion abnormalities. “In vivo” studies in pigs have shown that the IL-1β induces intimal thickening and coronary vasospastic responses to intracoronary serotonin or histamine, via ‘outside-to-inside’ signalling. In addition, in CAD patients who underwent elective coronary artery bypass grafting, the proinflammatory properties of the epicardial adipose tissue were significantly greater than those of the subcutaneous adipose tissue. However, this was not seen in plasma concentrations of various systemic inflammatory biomarkers.³

PVAT has different pathophysiological roles, depending on its location in the body, and modulates the vascular tone in a paracrine/autocrine manner, by releasing an array of vasoactive mediators, including adiponectin, NO, and hydrogen sulfide. Perivascular inflammation has been shown to be associated with enhanced coronary vasoconstrictor reactivity in patients with vasospastic angina (VSA). Increased coronary adventitial and PVAT inflammation, evaluated by F-fluorodeoxyglucose PET/CT, have been shown to be accompanied by enhanced adventitial vasa vasorum formation and Rho-kinase activity of circulating leukocytes, where the vasa vasorum serves as a conduit for inflammatory cells and cytokines, originating from the local inflamed adipose tissue, to the nearby coronary atherosclerotic lesions in the vascular wall.³

Cumulating data confirms the role of inflammation in patients with chest pain and myocardial infarction. In patients with typical angina, without CAD, serum concentrations of soluble CD40 ligand and tumour necrosis factor (TNF)-α were described to be significantly associated with a decrease in the myocardial perfusion reserve index (MPRI), during adenosine stress cardiac magnetic resonance (CMR), whereas serum concentrations of TNF-α and soluble intercellular adhesion molecule-1 (sICAM-1) were significantly associated with a MPRI reduction during Acetylcholine (Ach) stress CMR. Reduced MPRI was significantly correlated with both endothelium-dependent and -independent changes in coronary blood flow (CBF) in response to ACh and adenosine, respectively. The proinflammatory IL-1β/TNF-α/IL-6/CRP pathway is significantly associated with CMD in women with angina, but no obstructive CAD. Together, these observations suggest that chronic subclinical inflammation contributes to the development of CMD. The range of inflammatory mediators implicated in the pathogenesis of CMD and atherosclerotic cardiovascular diseases, goes beyond afore mentioned, and soluble urokinase-type plasminogen activator receptor (suPAR), is one of the novel inflammatory biomarkers involved in the inflammation in CMD. There are three possible explanations for the link between endothelium-dependent CMD and epicardial coronary atherosclerosis, based on the role of suPAR in their respective pathogenesis. First, the transcoronary production of suPAR in patients with endothelium-dependent CMD may reflect a local low-grade inflammatory state in the coronary circulation. Second, suPAR may be considered an active promoter of endothelium-dependent CMD, given that suPAR mediates the cleavage and inactivation of vasodilator peptides, such as calcitonin gene-related peptide. Third, suPAR may promote the development and progression of coronary atherosclerosis in a distinct milieu exposed to endothelium-dependent CMD, given his involvement in the macrophage foam cell formation, the migration and proliferation of VSMCs, and the formation of vulnerable plaques.⁴

Chronic low-grade vascular inflammation plays an important role in the mechanisms underlying CMD, especially in patients with diabetes, obesity, chronic inflammatory rheumatoid diseases, and heart failure with preserved ejection fraction (HFpEF).

Reduced CFR in obese patients without obstructive CAD is associated with increased plasma IL-6 and TNF-α concentrations, considering these proinflammatory adipokines contributing factor to the pathophysiology of CMD by inducing vascular inflammation and by disrupting the microvascular systems. For example, aging and obesity are known to induce a phenotype transition of PVAT to a proinflammatory state, by increasing the activity of a disintegrin and metalloproteinase 17, and the release of TNF-α in the adipose tissue, leading to impaired bradykinin-induced endothelium-dependent vasodilatation of the coronary arterioles, and thereby the development of CMD.⁴

Obesity also impairs the PVAT-mediated vascular function through several mechanisms involving EDRFs. Firstly, it promotes the recruitment of proinflammatory macrophages to PVAT, and impairs its vasodilator properties by reducing the endothelial and VSMC production of hydrogen sulfide, leading to microvascular endothelial dysfunction. Secondly, the obesity-associated hypoxia increases the expression of hypoxia-inducible factor-1α, which in turn induces adipose tissue fibrosis and local inflammation, with overproduction of leptin, resistin, IL-6 and TNF-α. These proinflammatory mediators reach the coronary microcirculation, promoting remote oxidative stress increase in the coronary arteriolar wall, followed by reduced NO bioavailability and impaired vasodilatation. ⁵

Systemic inflammation is also proposed as a new paradigm for the pathogenesis of HFpEF. Common HFpEF patient comorbidities, such as diabetes, hypertension and obesity, can elicit a systemic proinflammatory state. Elevated levels of inflammatory mediators, such as IL-6, TNF-α, soluble suppression of tumorigenicity 2 (ST2) and pentraxin 3, provoke coronary microvascular endothelial inflammation and reactive oxygen species (ROS) production, leading to reduced NO and cGMP content, and PKG activity in adjacent cardiomyocytes, increasing their resting tension. Consequently, stiff cardiomyocytes and interstitial fibrosis contribute to high diastolic left ventricular stiffness and the development of heart failure. In the context of potential mechanisms of the CMD-driven HFpEF, it was recently suggested that impaired H₂O₂/EDH factor-mediated vasodilatation in CMD is associated with cardiac diastolic dysfunction. High prevalence of endothelium-dependent and -independent CMD is associated with worse diastolic dysfunction and increased mortality.⁶

Moving from pathophysiology and clinical presentation towards treatment, the crucial question is, can we therapeutically target CMD, and if so, what is the optimal therapeutic treatment. At the present moment there is no established treatment for CMD in the clinical practice. However, in light of the established role of inflammation, the important question is: is there a place for anti-inflammatory drugs in the treatment of CMD?

The CANTOS randomised clinical trial demonstrates that canakinumab treatment significantly reduced the composite of non-fatal MI, non-fatal stroke, or cardiovascular death. The magnitude of the reduction of CV events was in correlation with the magnitude of the reduction of hs-CRP levels.² Other anti-inflammatory agent – colchicine was studied it the secondary prevention of CVD. The COLCOT and the LoDoCo2 clinical trials both demonstrated the efficacy and safety of low-dose 0.5 mg/day colchicine in patients with stable CAD. 

However, the therapeutic potential in CMD patients remains to be confirmed in large randomized clinical trials.